User:Yvonnedep/sandbox

Hydroamination is the addition of an N-H bond of an amine across a carbon-carbon unsaturated bond of an alkene, alkyne, diene, or allene. This process is a 100% atom economical and green method of preparing substituted amines because there are no unwanted by-products. Amines are attractive targets for organic synthesis in the fine-chemical, pharmaceutical, and agricultural industries. Hydroamination can be used intramolecularly to create heterocycles or intermolecularly with a separate amine and unsaturated compound. The development of catalysts for hydroamination remains an active area, especially for alkenes.

History
The first intramolecular hydroamination catalysts were reported by Tobin J. Marks in 1989 using rare-earth metals such as lanthanum, lutetium, and samarium with metallocene ligands. It was found that as the ionic radius of the metal increases, so does the rate of catalysis due to decreased steric interference from the ligands. In 1992, Marks developed the first chiral hydroamination catalysts by using a chiral auxiliary, which were the first hydroamination catalysts to favor only one specific stereoisomer. Chiral auxilaries on the metallocene ligands were used to dictate the stereochemistry of the product. The first non-metallocene chiral catalysts were reported in 2003, and used bisarylamido and aminophenolate ligands to give higher enantioselectivity.

Reaction Scope
Hydroamination has been used with a wide variety of amines and carbon-carbon unsaturated systems to yield more complex molecules at mild conditions with the use of various vastly different catalysts. Amines that have been investigated span a wide scope including primary, secondary, cyclic, acyclic, and anilines with diverse steric and electronic substituents. The carbon-carbon unsaturated bonds that have been investigated include alkenes, dienes, alkynes, and allenes. For intramolecular hydroamination, various aminoalkenes have been used.

Products
Addition across the unsaturated carbon-carbon bond can be Markovnikov or anti-Markovnikov depending on the catalyst. Interestingly, when considering the possibly of R/S chirality, four products can be obtained: Markovnikov with R or S and anti-Markovnikov addition with R or S. Although there have been many reports of catalytic hydroamination with a wide range of metals, there are far fewer describing enantioselective catalysis to selectively make one of the four possible products. Recently, there have been reports of selectively making the thermodynamic or kinetic product, which can be related to the racemic Markovnikov or anti-Markovnikov structures (see Thermodynamic and Kinetic Product below).

Metals used for Catalysis
Progress has been reported on the hydroamination of alkynes and alkenes using various catalysts. The first were made from lanthanides and late transition metals. Presently, hydroamination catalysts come in the form of practically every metal with equally diverse ligands. Catalysts have been reported using main group elements including alkali metals such as lithium, group 2 metals such as calcium , as well as group 3 metals such as aluminum  and indium. Furthermore, bismuth has also been proven to be an efficient metal center for this catalyzed transformation. In addition to these main group examples there has been extensive research conducted on the transition metals with reports of early, mid, and late metals, as well as first, second, and third row elements. The last realm of the periodic table that has been thoroughly investigated includes the lanthanides and actinides. Zeolites have also shown utility in hydroamination. The ligand systems utilized on these metals are more diverse than the metals themselves, such that ligands will not be discussed here, though the variety can be seen by exploring the references below.

Catalytic Cycle
The mechanism of metal-catalyzed hydroamination has been well studied. One particular system that has been well studied and used a general catalytic cycle is that by T.J. Marks and coworkers where a rare-earth metal was used to catalyze the intramolecular hydroamination of alkenes. First, the catalyst is activated by amide exchange, generating the active catalysis (i). Next, the alkene inserts into the Ln-N bond (ii). Finally, protonolysis occurs generating the cyclized product while also regenerating the active catalyst (iii). Although this mechanism depicts the use of a lanthanide catalyst, it is the basis for rare-earth, actinide, and alkali metal based catalysts. Late transition metal hydroamination catalysts have multiple models based on the regioselective determining step. The four main categories are (1) nucleophilic attack on an alkene or alkyne when coordinated to a metal, (2) nucleophilic attack on a coordinated allyl, (3) alkene insertion into a metal-hydride bond, and (4) insertion of the alkene into the metal-amide bond. Generic catalytic cycles for 1, 3, and 4 appear below with 2 being left out as it is analogous to 1 except there is an allyl coordinated instead of an alkene. Each of these catalytic cycles appear often in the literature and are supported through experimental data obtained from rate studies, isotopic labeling, and trapping of the proposed intermediates. As such, there is significant evidence to support each potential pathway, though the main determinant lies in the metal and ligand system applied in catalysis.

General Considerations
The hydroamination reaction is approximately thermodynamically neutral; there is a high activation barrier due to the repulsion of the electron-rich substrate and the amine nucleophile. The reaction also has a highly negative entropy, making it unfavorable at high temperatures. Consequently, catalysts are necessary for this reaction to proceed. Catalysts often have excellent turnover rates and turnover numbers. In general, intramolecular cyclizations occur at faster rates than intermolecular hydroaminations.

Selective Isolation of the Thermodynamic and Kinetic Product
In general, most hydroamination catalysts require elevated temperatures to function efficiently, and as such, the thermodynamic product is typically the only one observed. Recently, the isolation and characterization of the rarer and more synthetically valuable kinetic allyl amine product was reported. Both systems utilized allenes as their carbon source. One system utilized temperatures of 80 °C with a rhodium catalyst and aniline derivatives as the amine. The other reported system utilized a palladium catalyst at room temperature with a wide range of primary and secondary cyclic and acyclic amines. Both systems produced the desired allyl amines in high yield, which contain an alkene that can be further functionalized through traditional organic reactions.

Base catalyzed hydroamination
Strong bases catalyze hydroamination, an example being the ethylation of piperidine using ethylene: Such base catalyzed reactions proceed well with ethylene but higher alkenes are less reactive.

Hydroamination catalyzed by group (IV) complexes
Titanium and zirconium complexes catalyze inter-molecular hydroamination of alkynes and allenes. Both stoichiometric and catalytic variants were initially examined with zirconocene bis(amido) complexes. Titanocene amido and sulfonamido complexes catalyze the intra-molecular hydroamination of aminoalkenes via a [2+2] cycloaddition that forms the corresponding azametallacyclobutane, as illustrated in Figure 1. Subsequent protonolysis by incoming substrate gives the α-vinyl-pyrrolidine (1) or tetrahydropyridine (2) product. There is substantial experimental and theoretical evidence for the proposed imido intermediate and mechanism with neutral group IV catalysts.



Applications
Hydroamination has many real world applications due to the synthetically valuable products, as well as the greenness of the reaction. Functionalized allylamines, which can be produced through hydroamination, have extensive pharmaceutical applications. Some of these pharmaceutically important allyamines include Flunarizine and Naftifine. Flunarizine aids in the relief of migraines while naftifine acts to fight common fungus causing infections such as athlete's foot, jock itch, and ringworm. Though each of these pharmaceuticals already have a synthetic pathway to obtain the pure product, they all require multi-step purification and use of protecting groups, which go against the ideals of green chemistry. Recently, hydroamination has been utilized to synthesize another allylamine Cinnarizine in quantitative yield in just three hours. Cinnarizine treats both vertigo and motion sickness related nausea. This shows the great potential and promise that hydroamination has to real world syntheses.

Hydroamination is also particularly useful for synthesis of nitrogen-containing alkaloids. An example was the total synthesis of (-)-epimyrtine.